Hydroxyl compounds of the steroid series and process of making same



' the compounds of United States Patent HYDROXYL COMPOUNDS on THE srnnoin SERIES AND rnocnssor MAKING SAME Leopold Ruzicka, Hans Heusse'r, and Oskar .legcr, Zurich,

Inc Summit, N. J.

Application December 29, 1952, Serial No. 328,504

Switzerland, assignorsto Cilia Pharmaceuticallroducts,

No Drawing."

' Claims priority, application Switzerland February 21, 1952.

9 Claims C1. 260-1-3972) This inventionrelates to the manufacture of 9:11-dihydroxy compounds of the steroid series which possess in the rings B and C the following structures:

The compounds of type II can be converted in excellent yield into A F -7-keto-l l-hydrox'y-steroids by the ac-- tion of alkali,:.preferablyin a two-phase system.

The A -7-keto 1-1-hydroxy steroids, are important intermediate products for the manufacture of steroids which 7:8:9rl1-tetrahydroxy steroidsobtained are, if desired dehydrated to obtain 7'-keto-9: 11-dihydroxy steroids, preferably by treatment with alkali in a two-phase system.

The 7:ll-dihydroxy-8 :9- oxido steroids used as starting materials in the present case," belong to the cyclopentanopolyhydrophenanthrene or .polyhydrochrysene series. Especial importance is attached to the derivatives of ergostanejcholestane, copros'tane, sitostane, stigmastane,

spirostane, cholane, allocholane, pregnane, androstane and To thisclass of compounds belongs, for' 2,743,287 Patented Apr. 24, 1956 ice of solvents such as alcohols, ketones and organic acids, as for example acetic acid.,;

As isomerizing or dehydratingagents there are especiallyfsuitable more or less concentrated inorganic and organic. acids or their anhydrides, for example formic acid,- trichloracetic acid, hydrogen bromide, oxides or halides of phosphorus, such as phosphorus pentoxide or phosphorus tribro'mide,'boron trifluoride, inorganic salts, for examplezinc'chloride; ferric chloride or potassium bisulfate, and alkaline reacting agents, such as alkalies,

. alkaline earths or aluminar aetiocholane. In addition, thestarting materials may be a substituted in the nucleus or in the side chain, for exam- P161113, 5, 6, 17, 20- and/or 2l-position, by free or functionally converted hydroxyl groups or 0x0 groups,

such as 'acyloxy groups, for example acetoxy, propi onyloxy, benzoyloxy ortosyloxy groups, by alkoxy groups, for example methoxy or ethoxygroups, by acetalized 0X0 groups, by free or functionally converted carboxyl groups,

such as nitrile or esterified carboxyl groups or a lactone group, for example butenolide group. The starting materials may have any desired configurations and can also contain double bonds, as for example in 5:6- or 22:23-

position. U I I a I 'The starting materials of the present application are easily available by treatment of A unsaturated steroids, which contain in the positions 7 and 11 free or func: tionally converted hydroxyl groups, with oxidizing agents, as for example'chromium trioxideor organic or inorganic peracids.

As hydrolyzing agents there can be used dilute inorgani'c acids, forexample sulfuric acid, in the presence A two-phasesystem is understood to mean a reaction medium containing "liquids w'hic'h are not miscible with one another inall proportions, such as a mixture of aqueouscaustic potash solution andi'dioxane.

The, products of this invention are; intended for therapeutic application or for useas intermediate productsifor the'manu'fac'ture of therapeutically. useful compounds.

The following "examples illustratethe invention, the relation between part by weight and part by volume being the same as that between the gram and the cubic centimeter: I

, Exnrnple, J

, 1.1 parts by Weight of 'A a3fl-acetoxy-7z 1 l-dihydroxy- 8:9,foxido-ergostene are dissolved in amixture of .80 parts by volume ofg-lacial acetic acid and 80 parts by volume of dioxane andtreated with 0.3 part by volume of 2;N- sulfuric"acid. {The solution is maintained for 16 hours, I at 20 TC; and then diluted With a large quantity of ether,

The ethere'al layer is washed four times with water,,sodium bicarbonate solution and water, dried and evaporated.

The residue yields from acetone-hexane, followed-by recrystallization from-v-inethanol-water, pure A 3fi-acetoxy-7:8:9:1l-tetrahydroxy-ergostene of M. P. 250-252" C. ('[ixl =+8, in chloroform); yield 90 percent. This compound can be converted to f cortisone as ,follows: Thus inExample 5 there is disclosed the conversion of to n2 3/3-acetoxy-7-keto-9: 1 l-dihydroxy-ergo'stene and the conversion of the latter to A 5 -3BA1-diacetoxy- 7-keto ergos'tadiene (VI) described in Chemistry and In dustryf(1951) pages 1035 and 1036. This article shows the conversion of the "latter compound to .7zll-diketoergost22-e' n-3-p-yl-acetate (VII). From (VII), as shown by Tishler 'et'aL, JACS vol. 73, 2396-7 (1951), there is obtained 11:20 diketo -'allo pregnane 3 5 -.,yl-

acetate, which as shown byChemerda et al., JACSvoL,

73, 4052 (1951) and Rosenkrantz et al., JACS vol. .73, 4055 (1951) has been converted to cortisone.

The A2223 3/3 acetoxy 7:11 dihydroxy 8:9-

oxido-ergostene used 'as starting material, can be prepared as follows:

;5 parts by Weight of- A -3fi-acetoxy-7:1l-dihydroxy ergostadiene are dissolved in 800 parts by. volume of pure dioxane and treated with 67 'parts by volume of ethereal monoperphthalic acid containing, per part'by volume, 0.051 part by weight of active oxygen. The reaction .solution is maintained for 38 hours at 20 C. in

the dark and then dilutedwith ether, the ethereal -solu- 7 tion washed with water, sodium bicarbonate solution and again with water, dried and evaporated. The residue yields from methanol-water 4.1 parts by weight of A 9 3B acetoxy 7:11 -dihydroxy 4 8:9 oxido ergostene in the form of fine needles which melt at 147148 C.

([a] '=+15.5 in chloroform). I

'A f -3/3-acetoxy 7 2 1 1-dihydroxy-8 9-oxido I ergostene can" also be prepared by treating A3= -3,B-acetoxy- 7: 1l dihydroxy-ergostadiene in glacial acetic acid solution carefully-with the quantity of chromium trioxide corresponding to one equivalent. The 11 3527 :-1'1--- 3 p triacetoxy-8:9 oxido-ergostene, prepared from [3 -35- acetoxy-7:1l-dihydroxy-S:9-oxido-ergostene by acetylation in pyridine-acetic anhydride, melts. at l59-16l C.; [a] =+6 (in chloroform). v

Example :2 a

3 parts. by weight of A .-3;8-acetoxy-7:l-l-dihydroxy- 8:9-oxido-ergostene are dissolved in 300 partsby volume of absolute benzene, treated with 10 parts by volume of boron trifluoride-ether. complex and the whole maintained for two hours at 20 C. After standing for a short time, well formed leaflets separate from the solution. For working up, the solution is diluted with ether, washed with water, sodium bicarbonate solution and water, dried and evaporated. The residue yieldsfrom methanol-water 2.5 parts by weight of A -3B-acetoxy- 7-keto-9:ll-dihydroxy-ergostene of M. P. 269 C. ([a] =62 in chloroform).

The semicarbazone ofthis compoundmelts at- 247- 249 C. with decomposition.

The M -3,9 1 l-diacetoxy-7-keto-9-hydroxy-ergostene, obtained by acetylation with acetic anhydride in pyridine, melts at 191 C.; [q] =45 (in chloroform).

Example 3 3 parts by weight of A -3B-acetoXy-7:ll-dihydroxy- 8:9-oxido-ergostene are dissolvedin 800 parts by volume of glacial acetic acid and maintained'together with 100 parts by volume of 2 N-sulfuric acid for 16 hours at 20 C., then for one hour at 40 C. The customary working up of the reaction mixture yields 2 parts by weight of the A -3B-acetoxy-7rketo-9:l1-dihydroxy ergostene, described in Example 2, of M. P. 269 C.

This substance can be converted into the M 3fl,11-dihydroxy-7-keto-ergostadiene, advantageously in the following manner:

0.5 part by weight of A -3;8-acetoxy-9:ll-dihydroxy-7-keto-ergostene is dissolved in 75 parts by volume of dioxane and treated with a solution of 2.5 parts by weight of potassium hydroxide in .25 parts by volume of water, whereby two layers form. The reaction mixture is then boiled under refluxfor 2 /2 days. The cooled solution is diluted with much ether and washed until neutral with water. The crudeproduct obtained yields from acetone 0.34 part by weight of needles which melt at 207-208 C. After recrystallization three times, the

pure A -3i3:ll-dihydroxy-7-keto-ergostadiene melts at 209-210 C.;- [a] =-2 (in chloroform).

In ethanol solution, the compound shows in the ultraviolet absorption spectrum a maximum at 253 mp, log e=3.91.

Example 4 1 part by weight of A -3;9-acetoxy-7:ll-dihydroxy- Example 8 parts by weight of. A -35-acetoxy-7:8:9:ll-tetrahydroxy-ergostene are dissolved in 120 parts byyolume 4 as described in Example 4. After recrystallization from methanol-water, the reaction product melts at 269 C. It is A -3B-acetoxy-7-keto-9:ll-dihydroxy-ergostene, and can be converted into the A -3}3,ll-diacetoxy-7- keto-ergostadiene as follows: 1

5 parts by weight of A -3fi-acetoxy-7-keto-9:lldihydroxy-ergostene are dissolved in 1500 parts .by volume of dioxane and, together with 500 parts by volume of 10 per cent. aqueous caustic potash solution, boiled for 62 hours under reflux. The solution is diluted with a large quantity of ether and the ethereal layer worked up in the customary manner. The crude product obtained yields, after subsequent acetylation, 5 parts by weight of crude A -3fi:1l-diacetoxy-7-keto-ergostadiene, which, after recrystallization from methanol, yields 4.5 parts by weight of the pure preparation of M. P. l84-185 C.; [u] =+l2 (in chloroform); (ultraviolet absorption in absolute alcohol; A max.=253 m log e: 4.01).

Example 6 chloroform and washed with water, sodium bicarbonate of glacial acetic acid and maintained together with 8 parts by volume of an aqueous 48 per cent. hydrogen bromide solution, forone hour at 20" C.

The working up follows solution and water, dried and evaporated. The solid residue (0.58 part by weight) is recrystallized from methanol. The 3,8:l7B-diacetoxy-7-keto-9:ll-dihydroxyandrostane is obtained of M. P. 2675-268 C.;

. [a] :75 in chloroform. The substance exhibits in the ultraviolet spectrum a wide maximum at 285 m log 6:152. a

It can be converted into the A -3fl:1la:l7;8-trihydroxy-7-keto-androstane as follows:

0.37 part by weight of 3/3:l7/3-diacetoxy-7-keto-9:lldihydroxy-androstane is dissolved in 30 parts by volume of dio'xane, treated with a solution of 0.75 part by weight of potassium hydroxide in 15 parts by volume of water and the whole heated for 6 hours with stirring to C. After cooling, acidification is carried out with 1 part by volume of glacial acetic acid and the reaction solution is evaporated .under vacuum to dryness. The residue is subjected to grinding with 5 parts by volume of water. The insoluble material is then filtered off and washed with a little water. After recrystallization from a mixture of methanol and water, the filter residue yields A 35:11aml7B-trihydroxy-7-keto-androstene of M. P. 263- 267 C.; [u] =-25 in alcohol. The substance exhibits in the ultraviolet absorption spectrum a maximum at 254 mu; log 5:3.99.

Acetylation with pyridine and acetic anhydride leads to A -33:11a:17B-triacetoxy-7-keto-androstene of M. P. 143-145" C.; absorption maximum at 252 m log e=4.02.

The 35:17fi-diacetoxy 7:11 dihydroxy 8:9 oxido androstane used as starting material can be prepared as follows: p

0.81 part by weight of A -3,3:17/3-diacetoxy-7zl1- dihydroxy-androstene is dissolved in 40 parts by volume of obsolute, dioxane and treated with 4.25 parts by volume of an ethereal solution of monoperphthalic acid containing 0.0347 part by weight of active oxygen per part by volume and the whole allowed to stand for 5 days in the dark at +3 C. Dilution is then carried out with parts by volume of chloroform, followed by washing with 0.25-nornra1 sodium bicarbonate solution and water, drying and evaporation under vacuum. 0.88 part by weight is obtained of an oily residue which, on grinding with ether, crystallizes. It is the crude 3/3:l7/3-diacetoxy-7:l1- dihydroxy-8:9-oxido-androstene which can be recrystal- C.; [a] :+l0 in chloroform.

What is claimed is: 1. A process which comprises reacting a 7:11-dihydroxy-8z9-oxido steroid of the formula:

Where R stands for a hydrocarbon carboxylic acid radical containing from 2-7 carbon atoms and R stands for a member of the group consisting of a hydrocarbon carboxylic acid radical containing 2-7 carbon atoms and the ergostene side chain, with a mineral acid so as to produce the corresponding 7:8:92ll-tetrahydroxy and 9:11-dihydroxy-7-keto compounds.

2. A process which comprises reacting a A -3-R- 7:1I-dihydroXy-S:9-oXido-ergostene, R being a hydrocarbon carboxylic acid radical containing 2-7 carbon atoms, with a mineral acid so as to produce the corresponding 7:8:9z11 tetrahydroxy and 9:11 dihydroxy 7 keto compounds.

3. A process according to claim 2, wherein the starting compound is A -3-acetoxy-7: ll-dihydroxy-8:9-oxidoergostene.

4. A process which comprises reacting a 7:11-dihydroxy-8z9'oxido steroid of the formula:

wherein R stands for a hydrocarbon carboxylic acid radical containing from 2-7 carbon atoms and R1 stands for a member of the group consisting of a hydrocarbon car- 'boXylic acid radical containing 2-7 carbon atoms and the 5 ergostene side chain, with a member of the group consisting of a mineral acid and boron trifiuoride so as to produce the corresponding 9: 11-dihydroXy-7-keto compounds.

5. A process according to claim 4, wherein the starting compound is A -3R-7:l1-dihyd-roxy-8:9-oxido-ergostene, R being a hydrocarbon carboxylic acid radical containing 2-7 carbon atoms.

6. A process according'to claim 4, wherein the starting compound is A -3-acetoxy-7:11-dihydroxy-8:9-oxido ergostene.

7. A process which comprises reacting a A -'3-R- 7:8:9:11-tetrahydroxy-ergostene, wherein R stands for a hydrocarbon carboxylic acid radical containing 2-7 carbon atoms, with a member of the group consisting of a mineral acid and boron trifluoride so as to produce the corresponding 9:1l-dihydroXy-7-keto compounds.

8. A -3-R-7:8:9:11-tetrahydroXy-ergostene, wherein R stands for ahydrocarbon carboxylic acid radical containing 2-7 carbon atoms.

9. A -3,8-acetoxy-7 8 9: 1l-tetrahydroxy-ergostene.

References Cited in the file of this patent UNITED STATES PATENTS 2,602,769 Murray July 8, 1952 

1. A PROCESS WHICH COMPRISES REACTION A 7:11-DIHYDROXY-8:9-OXIDO STEROID OF THE FORMULA: 